The purpose of this bridging project is to investigate the intersection of the innate and adaptive immune responses to encapsulated bacteria. These pathways converge in the generation of antibodies to capsular polysaccharides by marginal zone B cells and in the mechanisms by which antibodies synergize with PRRs in facilitating microbial phagocytosis by macrophages. Existing funded programs in the laboratory have genetically defined the crucial role of MZB cells and complement C3 in generating antigen-specific antibody responses to repetitive polysaccharide antigens. These pathways will be the focus of our efforts to construct a comprehensive catalogue of the signaling responses that are elicited in the generation of antibodies to capsular polysaccharides by marginal zone B cells and C3' using the proteomic, genomic and forward genetic infrastructure developed by the GLUE consortium. These antibodies play a crucial role in the elimination of microbial pathogens. Long-standing, funded studies in the laboratory have revealed the role of Fc receptors in this process. Through the mechanism of the GLUE consortium we will now be able to investigate the synergy between Fc receptor, TLR and complement signaling pathways in mediating effective defenses against these pathogens.